The present invention relates to compounds that inhibit metalloproteinases, particularly matrix metalloproteinases and tumor necrosis factor-.alpha. convertase, and their pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs. The invention further relates to the uses of these compounds, salts, and prodrugs for the therapeutic treatment of humans or animals.
Matrix metalloproteinases ("MMPs") are a family of enzymes, including, but not limited to, collagenases, gelatinases, matrilysin, and stromelysins, which are involved in the degradation and remodeling of connective tissues. These enzymes are found in a number of cell types that are found in or associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and metastatic tumor cells. They also share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology.
Matrix metalloproteinases degrade the protein components of the extracellular matrix, i.e., the protein components found in the linings of joints, interstitial connective tissue, basement membranes, cartilage, and the like. These proteins include collagen, proteoglycan, fibronectin, and lamanin.
Collagen is the major structural protein of mammalian tissue, comprising one-third of the total protein in mammalian organisms, and it is an essential component of many matrix tissues, including cartilage, bone, tendons, and skin. Interstitial collagenases catalyze the initial (rate-limiting) cleavage of native collagen types I, II, III, and X. These enzymes cleave collagen into two fragments which spontaneously denature at physiological temperature. Denaturation of collagen involves conversion of the rigidly coiled helix to a random coil referred to as gelatin. These gelatin (denatured collagen) fragments are then subject to further cleavage and degradation by less specific enzymes. The net result of collagenase cleavage is thus the loss of structural integrity in the matrix tissue (collagen collapse), an essentially irreversible process.
The gelatinases include two distinct yet highly related enzymes: a 72-kiloDalton (kDa) enzyme and a 92-kiloDalton enzyme. The former is released by fibroblasts while the latter is released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts, and keratinocytes. Both enzymes degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectins (high molecular weight multifunctional glycoproteins found in soft connective tissue and basement membranes), and insoluble elastin (highly cross-linked hydrophobic proteins found in load bearing fibers of mammalian connective tissue).
Stromelysins (1 and 2) cleave a broad range of matrix substrates, including lamanin, fibronectins, proteoglycans, and collagen types IV and IX (non-helical).
Matrilysin (putative metalloproteinase or PUMP) also degrades a wide variety of matrix substrates, including proteoglycans, gelatins, fibronectins, elastins, and lamanin. Matrilysin has been found in mononuclear phagocytes, rat uterine explants, and tumor cells.
In normal tissues, the activity of matrix metalloproteinases is tightly regulated. As a result, the breakdown of connective tissue mediated by these enzymes is generally in a dynamic equilibrium with synthesis of new matrix tissue.
In a number of pathological disease conditions, however, deregulation of matrix metalloproteinase activity leads to the uncontrolled breakdown of extracellular matrix. These disease conditions include arthritis (e.g., rheumatoid arthritis and osteoarthritis), periodontal disease, aberrant angiogenesis, tumor metastasis and invasion, tissue ulceration (e.g., corneal ulceration, gastric ulceration, or epidermal ulceration), bone disease, HIV-infection, and complications from diabetes.
Administration of matrix metalloproteinase inhibitors has been found to reduce the rate of connective tissue degradation, thereby leading to a favorable therapeutic effect. For example, in Cancer Res., vol. 53, p. 2087 (1993), a synthetic matrix metalloproteinase inhibitor was shown to have in vivo efficacy in a murine model for ovarian cancer with an apparent mode of action consistent with inhibition of matrix remodeling. The design and uses of MMP inhibitors are reviewed, for example, in J. Enzyme Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry 29, 271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp. Opin. Ther. Patents, 5, 1287-1296 (1995); and Drug Discovery Today, 1, 16-26 (1996).
Matrix metalloproteinase inhibitors are also the subject of numerous patents and patent applications, including: U.S. Pat. No. 5,189,178; U.S. Pat. No. 5,183,900; U.S. Pat. No. 5,506,242; U.S. Pat. No. 5,552,419; U.S. Pat. No. 5,455,258; European Patent Application No. 0 438 223; European Patent Application No. 0 276 436; WIPO International Publication No. WO 92/21360; WIPO International Publication No. WO 92/06966; WIPO International Publication No. WO 92/09563; WIPO International Publication No. WO 96/00214; WIPO International Publication No. 95/35276; WIPO International Publication No. WO 96/27583, WIPO International Publication No. WO 96/33172, European Patent Application No. 0 757 984, and European Patent Application No 0 757 037.
Tumor necrosis factor-.alpha. ("TNF-.alpha.") is a cytokine which is produced as a 28-kDa precursor and released in an active 17-kDa form. This active form can mediate a large number of deleterious effects in vivo, including inflammation, fever, cardiovascular effects, haemorrhage, coagulation, and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration of TNF-.alpha. can cause cachexia and anorexia; accumulation of excess of TNF-.alpha. can be fatal.
TNF-.alpha. convertase is a metalloproteinase involved in the biosynthesis of TNF-.alpha.. Inhibition of TNF-.alpha. convertase inhibits production of TNF-.alpha..
Since excessive TNF-.alpha. production has been noted in several disease conditions characterized by MMP-mediated tissue degradation, including multiple sclerosis, arthritis, and cancer, compounds which inhibit both MMPs and TNF-.alpha. convertase are especially advantageous for the treatment or prophylaxis of disease conditions in which both mechanisms are involved. Although compounds that both inhibit MMP activity and TNF-.alpha. production have been disclosed in WIPO International Publication Nos. WO 94/24140 and WO 94/02466, there is still a need for effective MMP and/or TNF-.alpha. convertase inhibiting agents.
Because of their beneficial therapeutic effects, there is a need for effective inhibitors of metalloproteinase activity. The present invention is therefore directed to certain compounds that inhibit metalloproteinases, such as MMPs and TNF-.alpha. convertase, their pharmaceutically acceptable prodrugs, salts, and solvates, pharmaceutical compositions containing the same, and methods of using the same, as well as to methods and intermediates useful in their preparation. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description or may be learned from practice of the invention.
To achieve these and other advantages, the present invention provides a compound of formula I: ##STR2##
wherein Ar is an aryl group or a heteroaryl group; X is --NH--OH or --OH; R.sub.1 is H, --CH(R.sub.3)(R.sub.4), --C(O)R.sub.3, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein R.sub.3 is H or any suitable substituent and R.sub.4 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; R.sub.2 is CH.sub.2 -R.sub.5, wherein R.sub.5 is H or any suitable substituent, or wherein R.sub.5 and R.sub.4 are optionally substituted carbon atoms singly- or double-bonded to one another; or a pharmaceutically acceptable prodrug, salt, or solvate thereof.
The present invention also is directed to a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable prodrug, salt, or solvate thereof; and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient.
The present invention is further directed to a method of treating a mammalian disease condition mediated by metalloproteinase activity which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable prodrug, salt, or solvate thereof. The compound of formula I (or its pharmaceutically acceptable prodrug, salt, or solvate) may be administered in the form of a pharmaceutical composition, as described above. Additionally, the present invention is directed to a method of treating tumor growth, invasion, or metastasis; osteoarthritis; rheumatoid arthritis; osteoporosis; periodontitis; gingivitis; chronic dermal wounds; corneal ulceration: degenerative skin disorders; multiple sclerosis; stroke; atherosclerosis; glomerular disease; or a disease condition characterized by unwanted angiogenesis, such as diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas.
The present invention is still further directed to a method of inhibiting the activity of a metalloproteinase that comprises contacting the metalloproteinase with an effective amount of a compound of formula (I) or a pharmaceutically acceptable prodrug, salt, or solvate thereof, optionally, in the form of a pharmaceutical composition as described above.
As used in the present application, the following definitions apply, unless otherwise indicated:
An "alkyl group" is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
An "O-alkyl group" or "alkoxy group" is intended to mean an oxygen bonded to an alkyl group, wherein the alkyl group is as defined above.
A "cycloalkyl group" is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1.]heptyl, bicyclo[2.2.1.]hept-2-en-5-yl, bicyclo[2.2.2]octyl, bicyclo[3.2.1.]nonyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, indan-1-yl, indan-2-yl, tetralin-1-yl, tetralin-2-yl, adamantyl, and the like.
A "heterocycloalkyl group" is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
An "aryl group" is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like.
A "heteroaryl group" is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl, isobenzofuryl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl, and the like.
An "acyl group" is intended to mean a --C(O)--R.sub.5 -- radical, wherein R.sub.5 is any suitable substituent as defined below.
A "sulfonyl group" is intended to mean a --S(O)(O)--R.sub.5 -- radical, wherein R.sub.5 is any suitable substituent as defined below.
The term "suitable substituent" is intended to mean any of the substituents recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable substituents include, but are not limited to, oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups,
groups of formula (A) ##STR3##
wherein R.sub.a is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (B) ##STR4##
wherein R.sub.a is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (C) ##STR5##
wherein R.sub.b and R.sub.c are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (D) ##STR6##
wherein R.sub.d is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, or an acylamino group; and R.sub.e is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, an alkylamino group, or a dialkylamino group,
groups of formula (E) ##STR7##
wherein R.sub.f is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (F) ##STR8##
wherein R.sub.g and R.sub.h are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
groups of formula (G) ##STR9##
wherein R.sub.i is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (H) (defined below), or formula (K) (defined below),
groups of formula (H) ##STR10##
wherein R.sub.j is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, or a group of formula (A), formula (B), formula (C) or formula (D); and wherein R.sub.k is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F),
groups of formula (J) ##STR11##
wherein R.sub.l, is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (C), and
groups of formula (K) ##STR12##
wherein R.sub.m and R.sub.n are independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, or a dialkylamino group.
The term "suitable organic moiety" is intended to mean any organic moiety recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, and
groups of formulas (A), (B), (C), (D), (E), (F), (G), (H), (J), and (K), as defined above.
A "hydroxy group" is intended to mean the radical --OH.
An "oxo group" is intended to mean the divalent radical .dbd.O.
A "halo group" is intended to mean any of the radicals --F, --Cl, --Br, or --I.
A "cyano group" is intended to mean the radical --C.ident.N.
A "nitro group" is intended to mean the radical --NO.sub.2.
A "trialkylsilyl group" is intended to mean the radical --SiR.sub.p R.sub.q R.sub.s, where R.sub.p, R.sub.q, and R.sub.s are each independently an alkyl group.
A "carboxy group" is intended to mean a group of formula (B) wherein R.sub.a is hydrogen.
A "alkoxycarbonyl group" is intended to mean a group of formula (B) wherein R.sub.a is an alkyl group as defined above.
A "carbamoyl group" is intended to mean a group of formula (C) wherein R.sub.b and R.sub.c are both hydrogen.
An "amino group" is intended to mean the radical --NH.sub.2.
An "alkylamino group" is intended to mean the radical --NHR.sub.u, wherein R.sub.u is an alkyl group as defined above.
A "dialkylamino group" is intended to mean the radical --NR.sub.u R.sub.v, wherein R.sub.u and R.sub.v, which are the same or different, are each an alkyl group as defined above.
A "pharmaceutically acceptable prodrug" is intended to mean a compound that is converted under physiological conditions or by solvolysis to a compound of formula I.
A "pharmaceutically acceptable solvate" is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formula I.
Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of formula I in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In the case of solid formulations, it is understood that the inventive compounds may exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
A "pharmaceutically acceptable salt" is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.
Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxyenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, .gamma.-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acids such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid; or the like.
If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; cyclic amines such as piperidine, morpholine, and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
The inventive compounds may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention.
As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
In the compounds, compositions, and methods of the present invention, preferably R.sub.3 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --OR.sub.10, --SR.sub.10, C.ident.C--R.sub.10, --C(O)OR.sub.10, C(O)NHR.sub.10, wherein R.sub.10 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroarylgroup.
Preferred compounds according to the invention include compounds having the formula II: ##STR13##
wherein R.sub.1, R.sub.2 and X are as defined above and Z is a halogen group, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an O-alkyl group, an S-alkyl group, an aryl group, or a heteroaryl group.
Other preferred compounds include compounds of formula I where Ar is a heteroaryl group containing six ring atoms. More preferably, Ar is pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
Other preferred compounds include those where R.sub.5 is H and R.sub.4 is an alkyl group. Also preferred are those compounds where R.sub.5 is a heteroaryl group and those where R.sub.5 is --CHR.sub.6 R.sub.7, wherein R.sub.6 is H or any suitable substituent and R.sub.7 is ##STR14##
wherein R.sub.8 is any suitable substituent.
In the inventive compounds, it is also preferred that R.sub.4 is an alkyl group and R.sub.3 is an alkyl group, an O-alkyl group, or an S-alkyl group. More preferably, R.sub.3 is a --CH.sub.2 CH.sub.2 -- heteroaryl group, an --OCH.sub.2 -- heteroaryl group, or an --S--CH.sub.2 -heteroaryl group.
Other preferred compounds include those where R.sub.4 and R.sub.5 together form the group --CH.sub.2 CH.sub.2 --.
Inventive compounds of formula I wherein X is NHOH are preferably selected from those possessing inhibitory potencies (Ki's) against human gelatinase A (Gel A), human collagenase-3 (Coll-3), and/or human stromelysin-1 (Strom) of less than 50 nM, and more preferably of less than 5 nM. Still more preferably, compounds of formula I wherein X is NHOH are selected from those possessing Ki's against Gel A and/or Coll-3 of less than 0.2 nM and/or those possessing an inhibition selectivity as defined by the ratio of Ki for human collagenase-1 (HFC) and the Ki for Coll-3, of greater than 50.
Inventive compounds of formula I wherein X is OH are preferably selected from those possessing Ki's against Gel A of less than 1 .mu.M, more preferably less than 200 nM, and still more preferably less than 50 nM. Assays for determining Ki's are described in greater detail infra.
Particularly preferred compounds falling within formula I include:
2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxami de,
2(R)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxam ide,
2(R)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxam ide,
2(R)-1-[4-(4-Methylphenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxam ide,
2(R)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2-carboxa mide,
2(R)-1-[4-Phenoxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxamide,
2(R)-1-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxa mide,
2(R)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2 -carboxamide,
2(R)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2 -carboxamide,
2(R)-1-[4-(4-(Imidazol4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2- carboxamide,
2(R)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2- carboxamide,
2(R)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2- carboxamide,
2(R)-1-[4-(4-(2-(Dimethylamino)ethyl)phenoxy)benzenesulfonyl]-N-hydroxypipe ridine-2-carboxamide,
2(R)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxypiperidine-2-carboxamide ,
2(R), 3(S)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2 -carboxamide,
2(R), 3(S)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine-2 -carboxamide,
2(R), 3(S)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-3-methylpiperidine- 2-carboxamide,
2(R), 3(S)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpip eridine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpip eridine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpip eridine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpipe ridine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methylpipe ridine-2-carboxamide,
2(R), 3(S)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-3-methylpiperidine-2-c arboxamide,
2(R)-2-[4-(4-Bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hyd roxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hy droxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-4-yl)methyl]amino-N-hy droxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(imidazol-2-yl)methyl]amino-N-h ydroxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-2-yl)ethyl]amino-N- hydroxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-4-yl)ethyl]amino-N- hydroxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(pyrazol-3-yl)ethyl]amino-N-h ydroxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino- N-hydroxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylamino)ethyl]amino-N-hy droxy-3-methylbutanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hy droxy-2-cyclohexylacetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(imidazol-2-yl)ethyl]amino-N- hydroxy-2-cyclohexylacetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino- N-hydroxy-2-cyclohexylacetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hy droxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][2-(methylcarbamoyl)ethyl]amino- N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hy droxy-2-(1-methylpiperidin-4-yl)acetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-N-hy droxy-2-(1-acetylpiperidin-4-yl)acetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl][(2-(methylcarbamoyl)ethyl]amino -N-hydroxy-2-(1-methylpiperidin-4-yl)acetamide,
2(R), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N,3-dihydroxybuta namide,
2(R), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-metho xybutanamide,
2(R), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-(2-me thoxyethoxy)butanamide,
2(R), 3(R), 3(2'(S))-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[ (5-oxopyrrolidin-2-yl)methoxy]butanamide,
2(R), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-m ethylimidazol-2-yl)methoxy]butanamide,
2(R)-2-(4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(1-met hylpiperidin-4-yl)acetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-cycloh exylacetamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(tetra hydro-2H-pyran-4-yl)acetamide,
2(S), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-m ethylisoxazol-3-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyr id-2-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-m ethylimidazol-2-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-m ethylpiperidin-4-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[2-(d imethylamino)ethylsulfanyl]butanamide,
2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-me thylisoxazol-3-yl)methylsulfanyl]propanamide,
2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyri d-2-yl)methylsulfanyl]propanamide,
2(S)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-me thylimidazol-2-yl)methylsulfanyl]propanamide,
2(R), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N,3-dihydroxybuta namide,
2(R), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-metho xybutanamide,
2(R), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-(2-me thoxyethoxy)butanamide,
2(R), 3(R), 3(2'(S))-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[ (5-oxopyrrolidin-2-yi)methoxy]butanamide,
2(R), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-m ethylimidazol-2-yl)methoxy]butanamide,
2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(1-met hylpiperidin4-yl)acetamide,
2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methyl butanamide,
2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-cycloh exylacetamide,
2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-2-(tetra hydro-2H-pyran-4-yl)acetamide,
2(S), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-m ethylisoxazol-3-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyr id-2-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-m ethylimidazol-2-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-m ethylpiperidin-4-yl)methylsulfanyl]butanamide,
2(S), 3(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[2-(d imethylamino)ethylsulfanyl]butanamide,
2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-me thylisoxazol-3-yl)methylsulfanyl]propanamide,
2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(pyri d-2-yl)methylsulfanyl]propanamide,
2(S)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-me thylimidazol-2-yl)methylsulfanyl]propanamide,
2(R), 3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N,3-dihydroxybutana mide,
2(R), 3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methoxy butanamide,
2(R), 3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-(2-meth oxyethoxy)butanamide,
2(R), 3(R), 3(2'(S))-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5 -oxopyrrolidin-2-yl)methoxy]butanamide,
2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methylbu tanamide,
2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclohex ylacetamide,
2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclopen tylacetamide,
2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-cyclopro pylacetamide,
2(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-2-(tetrahy dro-2H-pyran-4-yl)acetamide,
2(S), 3(R)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-met hylisoxazol-3-yl)methylsulfanyl]butanamide,
2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(5-(hyd roxymethyl)isoxazol-3-yl)methylsulfanyl]propanamide,
2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(phenyl )methylsulfanyl]propanamide,
2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(4-fluo rophenyl)methylsulfanyl]propanamide,
2(S)-2-[4-(Pyrid-4-yl)oxybenzenesulfonyl](methyl)amino-N-hydroxy-3-[(1-meth ylimidazol-2-yl)methylsulfanyl]propanamide,
2(R)-2-[4-(4-Bromophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methylb utanamide,
2(R)-2-[4-(4-Chlorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methyl butanamide,
2(R)-2-[4-(4-Fluorophenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methyl butanamide,
2(R)-2-[4-(4-Methylphenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methyl butanamide,
2(R)-2-[4-(4-Methoxyphenoxy)benzenesulfonyl](methyl)amino-N-hydroxy-3-methy lbutanamide,
2(R)-2-[4-Phenoxybenzenesulfonyl](methyl)amino-N-hydroxy-3-methylbutanamide ,
2(R)-2-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-piperidine-2-carboxa mide,
2(R)-2-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy -3-methylbutanamide,
2(R)-2-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy -3-methylbutanamide,
2(R)-2-[4-(4-(Imidazol4-yl)phenoxy)benzenesulfonyl](methyl)amino-N-hydroxy- 3-methylbutanamide, and
2(R)-2-[4-(4-(2-(dimethylamino)ethyl)phenoxy)benzenesulfonyl](methyl)amino- N-hydroxy-3-methylbutanamide,
2(R)-1-[4-(4-Bromophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2 -carboxamide,
2(R)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine- 2-carboxamide,
2(R)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine- 2-carboxamide,
2(R)-1-[4-(4-Methylphenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine- 2-carboxamide,
2(R)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine -2-carboxamide,
2(R)-1-[4-Phenoxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2-carboxam ide,
2(R)-1-[4-(Biphenyl-4-yl)oxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine -2-carboxamide,
2(R)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-piperidine-2 -carboxamide,
2(R)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H -azepine-2-carboxamide,
2(R)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H -azepine-2-carboxamide,
2(R)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H- azepine-2-carboxamide,
2(R)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-hexahydro-1H- azepine-2-carboxamide,
2(R)-1-[4-(4-(2-(Dimethylamino)ethyl)phenoxy)benzenesulfonyl]-N-hydroxy-hex ahydro-1H-azepine-2-carboxamide,
2(R)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-hexahydro-1H-azepine-2- carboxamide,
2(R), 3(S)-1-[4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1 H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(4-Fluorophenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1 H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(4-Methoxyphenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hexahydro- 1H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Imidazol-1-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-he xahydro-1H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Imidazol-2-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-he xahydro-1H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Imidazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-he xahydro-1H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Pyrazol-4-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hex ahydro-1H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(4-(Pyrazol-3-yl)phenoxy)benzenesulfonyl]-N-hydroxy-3-methyl-hex ahydro-1H-azepine-2-carboxamide,
2(R), 3(S)-1-[4-(Pyrid-4-yl)oxybenzenesulfonyl]-N-hydroxy-3-methyl-hexahydro-1H- azepine-2-carboxamide, and pharmaceutically acceptable prodrugs, salts, and solvates thereof.
The present invention is further directed to methods of inhibiting metalloproteinase activity, for example in mammalian tissue, by administering a compound of formula I, or a pharmaceutically acceptable prodrug, salt, or solvate thereof. The activity of the inventive compounds as inhibitors of metalloproteinases, such as MMPs (including stromelysins, collagenases, gelatinases, and/or matrilysin) and/or TNF-.varies. convertase, may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in Anal. Biochem., vol. 147, p. 437 (1985); Anal Biochem., vol. 180, p. 110 (1989); FEBS, vol. 96, p. 263 (1992); and European Patent Application No. 0 606 046, the disclosures of which are incorporated herein by reference.
Administration of the compounds of formula I, or their pharmaceutically acceptable prodrugs, salts, or solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal. Preferably, the mode of administration is oral.
The inventive compounds of formula I, or their pharmaceutically acceptable prodrugs, salts, or solvates, may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan. Suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, and aerosols. Preferably, the pharmaceutical form is a tablet or capsule for oral administration. The pharmaceutical composition may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration. Illustrative examples of such methods include those described in Remington's Pharmaceutical Sciences, 18th edition (1990).
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of the formula I, or a pharmaceutically acceptable prodrug, salt, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units. An exemplary dosage unit for a mammalian host contains an amount of from 0.1 milligram up to 500 milligrams of active compound per kilogram body weight of the host, preferably 0.1 to 200 milligrams, more preferably 50 milligrams or less, and even more preferably about 10 milligrams or less, per kilogram of the host weight. The selected dose may be administered to a mammal, for example, a human patient in need of treatment mediated by inhibition of metalloproteinase activity, by any known method of administrating the dose including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion.
The amount of the inventive compounds, salts, solvates, and/or prodrugs to be administered will vary based upon a number of factors, including the specific metalloproteinase to be inhibited, the degree of inhibition desired, the characteristics of the mammalian tissue in which inhibition is desired, the metabolic stability and activity of the particular inventive compound employed, and the mode of administration. One skilled in the art may readily determine a suitable dosage according to methods known to the art. Preferably, the amount of inventive compound of formula I, or their pharmaceutically acceptable prodrugs, salts, or solvates, administered ranges from 0.1 mg/kg body weight to 100 mg/kg body weight per day.
The inventive compounds, and the salts, solvates, and prodrugs thereof, may be prepared by employing the techniques available in the art using starting materials that are readily available. Exemplary methods of preparing the inventive compounds are described below. In the following schemes, unless otherwise indicated, R.sub.1, R.sub.2, and Ar are as defined above. ##STR15##
As illustrated in Scheme 1, hydroxamic acids of formula Ia (compounds of formula I where X is --NH--OH) can be prepared by reacting the corresponding carboxylic acids of formula Ib (compounds of formula I where X is --OH) with hydroxylamine in the presence of a suitable peptide coupling reagent, for example, 1,1'-carbonyldimidazole, N-(dimethylaminopropyl)-N'-ethyl carbodiimide, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or propanephosphonic anhydride in an inert polar solvent, such as dimethylformamide. Alternatively, compounds of formula III can be reacted with hydroxylamine in a suitable solvent mixture, such as THF/t-butanol/dichloromethane or water/dichloromethane, preferably at 0.degree. C., to give hydroxamic acids of formula I. Compounds of formula III are generally prepared, in a form directly useful for further reaction without isolation, by allowing carboxylic acids of formula Ib to react with thionyl chloride or oxalyl chloride, preferably in the presence of a catalytic amount of dimethylformamide, in dichoromethane solvent at -78.degree. C. to room temperature.
Alternatively, the coupling reactions described above may be carried out with compounds of formula Ib (or III) and O-protected derivatives of hydroxylamine (where Pg is a suitable protecting group, such as benzyl, tert-butyl, t-butyldimethylsilyl, or t-butyidiphenylsilyl) to give compounds of formula IV. Deprotection of compounds of formula IV using conventional methods (for example, see "Protective Groups in Organic Synthesis", T. W. Greene and P. G. M. Wuts, Wiley-Interscience 1991, the disclosure of which is incorporated herein by reference) provides compounds of formula Ia. ##STR16##
As shown in Scheme 2, carboxylic acids of formula Ib can be prepared by reacting N-substituted-.alpha.-amino acids of formula V with arylsulfonyl chlorides of formula VI, under biphasic basic conditions as described, for example, in "The Chemistry of the Amino Acids", J. P. Greenstein and M. Winitz, Robert E. Krieger Publishing Company, 1984, p. 886-889, the disclosure of which is incorporated herein by reference.
Alternatively, carboxylic acids Ib can be prepared by reacting N-substituted-.alpha.-amino acid derivatives VII, where Pg is any suitable protecting group as described, for example, in "Protective Groups in Organic Synthesis", T. W. Greene and P. G. M. Wuts, Wiley-Interscience 1991 (the disclosure of which is incorporated herein by reference), with aryl sulfonyl chlorides VI to give sulfonamides VIII under any of a variety of reaction conditions that have been reported in the literature for the sulfonylation of amino acid derivatives (see, for example, "The Chemistry of the Amino Acids", J. P. Greenstein and M. Winitz, Robert E. Krieger Publishing Company, 1984, p. 886-889). Deprotection of VIII to give the acids Ib can be carried out as appropriate to the protecting group Pg. As is evident to those skilled in the art, manipulations of functionality in the groups R.sub.1, R.sub.2, and/or Ar may be readily effected at the stage of VII prior to the deprotection of VIII to Ib. Amino acids V are commercially-available, or can be prepared according to methods familiar to those skilled in the art. ##STR17##
In cases where the N-substituted .alpha.-amino acid of formula V is not readily available, the sequence shown in Scheme 3 can be employed to prepare compounds of formula VIII. In this case, protected .alpha.-amino acids of formula IX are sulfonylated as described above to provide sulfonamides of formula X. Treatment of X with an alkylating agent R.sub.2 -X in the presence of a suitable base, such as potassium carbonate or sodium hydride, in a aprotic solvent, such as N,N-dimethylformamide, at 0.degree. C. to 60.degree. C., preferably at 25.degree. C., for 1 to 24 h provides compounds of formula VIII. ##STR18##
In some cases, elaboration of the R.sub.1 group in compounds of formula X is advantageous; one such sequence is outlined in Scheme 4, above. In Scheme 4, R.sub.10 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, and Y is oxygen or sulfur. The reaction scheme proceeds as follows. Sulfonylation of D-.alpha.-amino-.beta.-hydroxy amino esters of formula XI (e.g., esters of D-serine when R.sub.4 is H, and esters of D-allo-threonine when R.sub.4 is Me) with sulfonyl chlorides of formula VI as described above provides compounds of formula X-a. Treatment of sulfonamides of formula X-a with diethyl azodicarboxylate and triphenylphosphine in a suitable inert solvent, such as tetrahydrofuran, at 0.degree. C. to 50.degree. C. for 1 to 24 h provides sulfonyl aziridines of formula XII. Treatment of aziridines XII with alcohols R.sub.10 --OH (i.e., where R.sub.3 is --OR.sub.10) or thiols R.sub.10 --SH (i.e., where R.sub.3 is --SR.sub.10) in the presence of a suitable acid catalyst, such as boron trifluoride etherate, in an inert solvent such as dichloromethane or 1,2-dichloroethane, for 0.5 to 48 h at 0.degree. C. to 60.degree. C., preferably at 25.degree. C. provides compounds of formula X-b. ##STR19##
Aryl sulfonyl chlorides VI are most readily available by chlorosulfonylation of the corresponding aryl phenyl ethers XIII, as outlined in Scheme 5 above. In general, treatment of XIII with a little over one molar equivalent of chlorosulfonic acid in a suitable inert solvent, such as 1,2-dichloroethane or dichloromethane, at -20.degree. C. to 25.degree. C. for a period of one to twenty-four hours generates the corresponding sulfonic acid intermediate XIV. Without isolation, XIV can be further converted to the sulfonyl chloride VI by reaction with a chlorinating agent, such as oxalyl chloride or thionyl chloride, and optionally cataltyic DMF. In some cases, excess chlorosulfonic acid is effective at converting XIII directly to VI via the intermediacy of XIV. Compounds of the formula XIII are commercially-available or may be readily prepared by those skilled in the art from commercially-available materials by the Ullman reaction.
Other compounds of formula I may be prepared by methods known to those skilled in the art in a manner analogous to the general procedures described above. Specific examples of methods used to prepare the inventive compounds are described below along with illustrative preferred embodiments of the inventive compounds of formula I, or their pharmaceutically acceptable prodrugs, salts, or solvates.
The following specific examples are intended to be illustrative of the invention and should not be construed as limiting the scope of the invention as defined by the appended claims. These examples include preferred embodiments of the inventive compounds.